Project Summary The blossoming pharmaceutical field of protein-based ?biologic? drugs has been limited by the immunogenicity these agents can provoke from recipients, presenting an unmet medical need for methods to induce tolerance to these agents. We have recently demonstrated in mice that exposure of nave T cells to interferon beta can favor their differentiation into either pro-inflammatory Th1 cells or tolerogenic FOXP3+ regulatory T cells (Tregs), depending on the time interval between interferon exposure and T cell activation. Thus, we postulate that appropriately-timed interferon beta pretreatment can drive T cells into a tolerogenic phenotype upon subsequent exposure to a foreign antigen, such as a biologic drug. We propose to evaluate in humans the effect of in vivo exposure to interferon beta by evaluating the nave T cells from multiple sclerosis patients who receive this cytokine as part of their regular medical care. We will evaluate the phenotype such cells differentiate into upon activation, as well as their overall transcriptome, at different time points following interferon exposure, to define the appropriate time interval for interferon pretreatment to induce Tregs in humans. We also propose to treat healthy and colitic mice with interferon beta prior to exposure to exogenous antibodies to demonstrate that interferon pretreatment can reduce the immunogenicity of the latter. This work will serve as a necessary preclinical model to support the application of interferon pretreatment as a mechanism to reduce biologic drug immunogenicity in a future clinical trial.